US12220483B2ActiveUtilityA1

Liposome compositions comprising weak acid drugs and uses thereof

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Assignee: PHARMOSA BIOPHARM INCPriority: Jul 24, 2017Filed: Mar 18, 2024Granted: Feb 11, 2025
Est. expiryJul 24, 2037(~11 yrs left)· nominal 20-yr term from priority
Inventors:Pei KanYi-Fong LinKo Chieh Chen
A61K 9/1271A61K 9/1278A61K 31/5585A61K 47/02A61P 11/06A61K 31/185A61K 47/12A61K 9/127
78
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Claims

Abstract

The present invention relates to a pharmaceutical composition comprising a weak acid drug, with the use of a bicarbonate salt to achieve a high incorporation of the drug into the liposome and a better therapeutic efficacy. Also disclosed is a method for treating a respiratory disease using the pharmaceutical composition disclosed herein.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
       1. A method for treating a respiratory disease, comprising the steps of administering a pharmaceutical composition comprising liposomes, said liposomes comprising:
 (a) a lipid bilayer, comprising vesicle-forming lipid; and 
 (b) an internal aqueous medium inside the lipid bilayer, comprising a bicarbonate salt and a weak acid drug with a pKa between about 1 to about 6,
 wherein the liposomes are suspended in an external medium, the concentration of the bicarbonate salt is about 50 mM to less than about 1000 mM, the pH of the external medium is above the pKa of the weak acid drug and the vesicle-forming lipid comprises a mixture of a first phospholipid and a second phospholipid or a mixture of a first phospholipid and a charged lipid, and 
 wherein the encapsulation efficiency of the weak acid drug is at least about 50%. 
 
 
     
     
       2. The method of  claim 1 , wherein the molar ratio of the weak acid drug to the bicarbonate salt is from about 0.1:1 to about 1:1. 
     
     
       3. The method of  claim 1 , wherein the concentration of the bicarbonate salt is about 250 mM to about 800 mM. 
     
     
       4. The method of  claim 1 , wherein the encapsulation efficiency of the weak acid drug is at least 80%. 
     
     
       5. The method of  claim 1 , wherein the first phospholipid is phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidic acid (PA), phosphatidylethanolamine (PE), phosphatidylserine (PS) or any combination thereof, the second phospholipid is a PEG modified phospholipid, a positively charged or a negatively charged phospholipid, and the charged lipid is a positively charged or a negatively charged lipid. 
     
     
       6. The method of  claim 5 , wherein the first phospholipid is HSPC, DSPC, DPPC, DMPC or any combination thereof and the second phospholipid is DSPG, DPPG, DMPG, PEG-DSPE, or any combination thereof and charged lipid is stearylamine, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 3ß-[N-(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol (DC-Cholesterol), N 4 -Cholesteryl-Spermine (GL67), dimethyldioctadecylammonium (DDAB), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), ethylphosphocholine (ethyl PC) or any combination thereof. 
     
     
       7. The method of  claim 1 , wherein the vesicle-forming lipid further comprises a sterol that is cholesterol, cholesterol hexasuccinate, ergosterol, lanosterol, or any combination thereof. 
     
     
       8. The method of  claim 7 , wherein the first phospholipid is phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidic acid (PA), phosphatidylethanolamine (PE), phosphatidylserine (PS) or any combination thereof, the second phospholipid is a PEG modified phospholipid, a positively charged or a negatively charged phospholipid, and the charged lipid is a positively charged or a negatively charged lipid, and the mole percent of the first phospholipid: cholesterol: the second phospholipid or the charged lipid is 50-70:20-45:0.1-10. 
     
     
       9. The method of  claim 7 , wherein the first phospholipid is HSPC, DSPC, DPPC, DMPC or any combination thereof, the second phospholipid is DSPG, DPPG, DMPG, PEG-DSPE, or any combination thereof and the sterol is cholesterol. 
     
     
       10. The method of  claim 9 , wherein the mole percent of the first phospholipid: cholesterol: the second phospholipid is 50-70:20-45:0.1-10. 
     
     
       11. The method of  claim 7 , wherein the first phospholipid is HSPC, DSPC, DPPC, DMPC or any combination thereof, the charged lipid is stearylamine, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 3ß-[N-(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol (DC-Cholesterol), N 4 -Cholesteryl-Spermine (GL67), dimethyldioctadecylammonium (DDAB), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), ethylphosphocholine (ethyl PC) or any combination thereof, the sterol is cholesterol. 
     
     
       12. The method of  claim 11  wherein the mole percent of the first phospholipid: cholesterol: the charged lipid is 50-70:20-45:0.1-10. 
     
     
       13. The method of  claim 1 , wherein the bicarbonate salt is potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, magnesium bicarbonate, cesium bicarbonate, lithium bicarbonate, nickel bicarbonate, ferrous iron bicarbonate or any combination thereof. 
     
     
       14. The method of  claim 1 , wherein the weak acid drug is a prostaglandin, a steroid, a non-steroidal anti-inflammatory drug (NSAID), or an anticoagulant. 
     
     
       15. The method of  claim 14 , wherein said prostaglandin is Prostaglandin E1 (PGE1), Prostaglandin E2 (PGE2), Epoprostenol, Iloprost, Beraprost, MRE-269, prostacyclin, treprostinil or Ralinepag. 
     
     
       16. The method of  claim 14 , wherein said steroid is hydrocortisone, methylprednisolone, betamethasone or dexamethasone. 
     
     
       17. The method of  claim 14 , wherein said NSAID is Piroxicam, Meloxicam, Lornoxicam, ketorolac or diclofenac. 
     
     
       18. The method of  claim 10 , wherein said weak acid drug is Prostaglandin E1 (PGE1), Prostaglandin E2 (PGE2), Epoprostenol, Iloprost, Beraprost, MRE-269, prostacyclin, treprostinil, Ralinepag, hydrocortisone, methylprednisolone, betamethasone, dexamethasone, Piroxicam, Meloxicam, Lornoxicam, ketorolac, diclofenac or warfarin. 
     
     
       19. The method of  claim 12 , wherein said weak acid drug is Prostaglandin E1 (PGE1), Prostaglandin E2 (PGE2), Epoprostenol, Iloprost, Beraprost, MRE-269, prostacyclin, treprostinil, Ralinepag, hydrocortisone, methylprednisolone, betamethasone, dexamethasone, Piroxicam, Meloxicam, Lornoxicam, ketorolac, diclofenac or warfarin. 
     
     
       20. A method for treating a respiratory disease, comprising the steps of administering a pharmaceutical composition comprising liposomes, said liposomes comprising:
 (a) a lipid bilayer, comprising a mixture of a first phospholipid that is HSPC, DSPC, DPPC, DMPC or any combination thereof, a second phospholipid that is DSPG, DPPG, DMPG, PEG-DSPE, or any combination thereof and cholesterol or a first phospholipid, that is HSPC, DSPC, DPPC, DMPC or any combination thereof, a charged lipid that is stearylamine, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), 3ß-[N-(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol (DC-Cholesterol), N 4 -Cholesteryl-Spermine (GL67), dimethyldioctadecylammonium (DDAB), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), ethylphosphocholine (ethyl PC) or any combination thereof and cholesterol; and 
 (b) an internal aqueous medium inside the lipid bilayer, comprising 50 mM to 800 mM bicarbonate salt and a prostaglandin,
 wherein the liposomes are suspended in an external medium, the pH of the external medium is above the pKa of the prostaglandin, and the encapsulation efficiency is over 80%.

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